ABSTRACT: Remote heating of magnetic nanoparticles (MNPs) with an alternating magnetic field (AMF) has been widely explored as a therapeutic approach. Most often, the heat generated is used to thermally ablate target tissue or to trigger the release of drugs from thermally-responsive nanoparticles. Remote activation of the therapeutic effect is an attractive feature because it provides physicians with dynamic control over both timing and dose of the treatment. Magnetic fields offer an enormous opportunity to trigger a therapeutic effect remotely to any tissue within the body, as the lack of magnetism of biological materials allows for extremely specific delivery of energy to magnetic nanomaterials with insignificant absorption by the body. Unfortunately, due to the diffraction limit, it is impractical to focus the 100-500kHz AMF that optimally couples to magnetic nanomaterias to the millimeter-scale regions of interests. As a result, heating occurs wherever MNPs are located and is directly proportional to MNP concentration, which can vary significantly across a target tissue and thus can lead to incomplete tissue ablation. Further, if MNPs are not perfectly confined within a target area, surrounding normal tissue can also be damaged. Therefore, AMF-induced heating of MNPs would benefit tremendously from the ability to more precisely control the location and extent of heating. In this study, rather than attempt to focus the AMF, and be constrained by the unfavorable diffraction-limited focusing, we instead borrow a concept from magnetic resonance imaging (MRI) and use an overlaid-static field to achieve improved spatial resolution. Remote heating of MNPs can be spatially confined to a millimeter-sized focal spot in 3-dimensional space by overlaying the AMF with a static, non-uniform magnetic field with a sharply defined magnetic field zero at its center. The fixed field limits the responsiveness of MNPs to the AMF to locations at or near the position of the zero magnetic field. In this proposal, we plan to systematically validate and characterize a prototype Targeted Magnetic Heating Device (TMHD) and demonstrate spatially controlled thermal ablation and drug release from thermally-responsive nanovesicles. The specific aims for this proposal are (1) Prepare MNPs and MNP-loaded, thermally-responsive nanovesicles; (2) Characterize the Targeted Magnetic Heating Device (TMHD); (3) Demonstrate TMHD-triggered cytotoxicity in cell culture.